The purpose of this project is to elucidate the neural mechanisms and principles of treatment of chronic pain syndromes, with particular attention to the drug treatment of pain caused by nerve injury. Because of growing evidence from animal studies that neuropathic pain may be mediated by N-methyl-D-aspartate (NMDA) receptor-mediated activation of spinal cord neurons, a focus of recent work has been the evaluation of NMDA receptor antagonists in patients with neuropathic pain. Twenty-six patients (13 with painful diabetic neuropathy and 13 with postherpetic neuralgia) completed a placebo-controlled double-blind crossover trial of the NMDA receptor antagonist dextromethorphan, 400mg/day (approximately 3 1/2 times the maximum dose recommended for dextromethorphan as a cough suppressant). In the diabetic patients, pain was reduced by a mean of 24% relative to placebo (p = 0.014); 7/13 patients reported moderate or greater relief with dextromethorphan, compared to 0/13 with placebo. Pain was minimally affected by dextromethorphan in the patients with postherpetic neuralgia, however. Drug side effects, including sedation, confusion, and dysphoria, caused four patients to drop out, but an acceptable dose regimen could be found for the other patients. This is the first study showing that chronic treatment with an NMDA receptor antagonist relieves pain and is reasonably well tolerated. This result supports the hypothesis, generated in Bennett's CCI neuropathic rat model, that NMDA receptor mechanisms are important in the generation of neuropathic pain. If confirmed by additional studies, this clinical trial makes a new treatment available for patients with neuropathic pain syndromes, including peripheral neuropathy in diabetes, AIDS, and other systemic diseases, and orofacial syndromes such as traumatic nerve injury, reflex sympathetic dystrophy, and atypical facial pain. Current studies in patients with neuropathic pain are comparing dextromethorphan to memantine, another NMDA receptor antagonist, and placebo, with the intent of confirming the efficacy of dextromethorphan, and finding a more effective and safer alternative. Other work this year included four studies of the drug effects and sensory mechanisms in the intradermal capsaicin model in normal volunteers, which transiently reproduces symptoms resembling neuropathic pain, and collaborative studies with other centers of acupuncture, mexiletine, and amitriptyline in pain caused by AIDS-related neuropathy, and of morphine in post-herpetic neuralgia. Our work in developing methods for doing clinical studies of chronic pain has resulted in 10 publications this year on analgesic clinical trial methodology for patients with pain caused by neurological disease, surgery, arthritis, cancer, and sickle cell disease, in draft guidelines for the FDA, and in a course on clinical trials at the upcoming Eighth World Congress on Pain.